Cyclophilin inhibition protects against experimental acute kidney injury and renal interstitial fibrosis

Khai Gene Leong, Elyce Ozols, John Kanellis, Shawn S. Badal, John T. Liles, David J. Nikolic-Paterson, Frank Y. Ma

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11 Citations (Scopus)

Abstract

Cyclophilins have important homeostatic roles, but following tissue injury, cyclophilin A (CypA) can promote leukocyte recruitment and inflammation, while CypD can facilitate mitochon-drial-dependent cell death. This study investigated the therapeutic potential of a selective cyclo-philin inhibitor (GS-642362), which does not block calcineurin function, in mouse models of tubular cell necrosis and renal fibrosis. Mice underwent bilateral renal ischemia/reperfusion injury (IRI) and were killed 24 h later: treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. In the second model, mice underwent unilateral ureteric obstruction (UUO) surgery and were killed 7 days later; treatment with 10 or 30 mg/kg/BID GS-642362 (or vehicle) began 1 h before surgery. GS-642362 treatment gave a profound and dose-dependent protection from acute renal failure in the IRI model. This protection was associated with reduced tubular cell death, including a dramatic reduction in neutrophil infiltration. In the UUO model, GS-642362 treatment signifi-cantly reduced tubular cell death, macrophage infiltration, and renal fibrosis. This protective effect was independent of the upregulation of IL-2 and activation of the stress-activated protein kinases (p38 and JNK). In conclusion, GS-642362 was effective in suppressing both acute kidney injury and renal fibrosis. These findings support further investigation of cyclophilin blockade in other types of acute and chronic kidney disease.

Original languageEnglish
Article number271
Number of pages17
JournalInternational Journal of Molecular Sciences
Volume22
Issue number1
DOIs
Publication statusPublished - Jan 2021

Keywords

  • Acute kidney injury
  • Cell death
  • Chronic kidney disease
  • Cyclophilin
  • Inflammation
  • Mac-rophage
  • Neutrophil
  • Renal fibrosis

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